Systems, devices, and methods for sample integrity verification

ABSTRACT

The devices, systems, and methods disclosed herein provide sample verification capabilities in a single device or system. Devices are disclosed herein. Systems including these devices are also provided. These devices and systems may be configured for verifying sample integrity prior to a subject leaving a sample collection site so that any further samples or other corrective action can occur without having to make a separate visit.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/210,968 filed Aug. 27, 2015, U.S. Provisional PatentApplication Ser. No. 62/237,527 filed Oct. 5, 2015, U.S. patentapplication Ser. No. 14/631,776 filed Feb. 25, 2015 which claimspriority to U.S. Provisional Application Ser. No. 61/944,557 filed Feb.25, 2015, and U.S. patent application Ser. No. 15/242,171 filed Aug. 19,2016, which claims priority to PCT Application Ser. No. PCT/US15/17581filed Feb. 25, 2015, which claims priority to U.S. ProvisionalApplication Ser. No. 61/944,557 filed Feb. 25, 2014, the disclosures ofwhich are all hereby fully incorporated by reference in their entiretyfor all purposes.

BACKGROUND

Analysis of biological samples from a subject may be important forhealth-related diagnosing, monitoring, or treating of the subject. Avariety of methods are known for the analysis of biological samples.However, in order to provide better diagnosis, health monitoring, ormedical treatment of subjects, it is desirable to also have a highquality sample or at least a minimum quality sample collected from thesubject for analysis.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

SUMMARY

Applicants disclose herein multifunctional devices and systems. Usingsuch devices and systems, measurements may be made, for example, on abiological sample, or on more than one biological sample. Optionally,some embodiments may take measurements from at least one biological andat least one non-biological object. Measurements made usingmulti-functional devices or systems disclosed herein, or made usingmethods disclosed herein, may further be made in concert with, or priorto, or following, other measurements made on the same biological sampleor samples, or on a biological sample or samples derived from, obtainedalong with, or similar to, a biological sample or samples measured usingthe devices, systems, or methods disclosed herein.

In at least one embodiment, it is desirable to verify the samplecollected from the subject for one or more sample characteristics beforethe subject has departed from the collection facility. In this manner ifthere are any issues with sample quality, sample integrity, samplevolume, or any other characteristics, the issue(s) can be remediedwithout having to recall the subject from a location away from thecollection facility. Optionally, the sample can be verified as part ofthe collection event, wherein the subject does not depart from thecollection station until verification has occurred.

In at least one embodiment, the verification occurs in a device externalto a sample imager. Optionally, some embodiments may include at leastone processor in the sample imager that can verify the sample collected.

Accordingly, Applicants provide devices that are configurable foroperation in one or more modes. One mode may be a sample verificationmode of multiple characteristics. Other modes may be image capture mode,test mode, single characteristic verification mode,

Applicants further provide systems comprising such devices. Theconfigurations of systems disclosed herein may be changed, so that asystem may be configured for operation in a spectroscopy mode at onetime, and may be configured for operation in a fluorescence mode atanother time, and may be configured for operation in a luminescence modeat yet another time.

In embodiments, such devices may comprise a sample container supportsuch as but not limited to a sample container holder configured to holda sample for observation, measurement, or analysis, e.g., for opticalobservation, measurement, or analysis. In embodiments, such devices maycomprise a sample handling device configured to transport a sample, asample holder, or both, to a location suitable for observation,measurement, or analysis, e.g., for optical observation, measurement, oranalysis. In embodiments, a sample handling device may comprise a fluidhandling device or system, or may be configured to operate inconjunction with a fluid handling device or system. In embodiments, asample handling device may comprise a gantry, or may be configured tooperate in conjunction with a gantry. In embodiments, a fluid handlingdevice may comprise, or be configured to operate in conjunction with, agantry.

In embodiments, a device as disclosed herein may include a light source,and may include optical elements (e.g., one or more of a lens, agrating, an aperture, a filter, a polarizer, or other element orelements) configured to provide light for illuminating a sample. Inembodiments, light source for illuminating a sample may be emitted froma light source and then pass directly to the sample. In embodiments, alight source configured for illuminating a sample may be emitted from alight source and may then pass to, onto, through, or by, a grating, amirror, a lens, a filter, a pin-hole, or other optical element ordevice, prior to passing to the sample. In embodiments, light forilluminating a sample may be emitted from a light source and may besplit into two or more light paths; said two or more light paths may bedirected along the same, or along similar, or along different, paths. Inembodiments, one or more of said two or more light paths may be directedto a sample.

In embodiments, a device as disclosed herein may comprise a mirror orother reflective surface. It will be understood that a mirror may beconfigured to reflect some, or may be configured to reflectsubstantially all, of the light impinging on that mirror from a lightsource, or a mirror, or a lens, or a grating, or other source.

In embodiments, a device as disclosed herein may comprise a diffractiveelement, e.g., diffraction grating, diffractive lens, diffuser, beamsplitter, corrective lens, or other surface or element configured todiffract light. In embodiments, a device as disclosed herein maycomprise a pin-hole, or slit, or plurality of pin-holes, a slit orslits, or other optical elements configured to provide diffraction orinterference with light. Diffraction (and interference) may affecttransmitted, or reflected light (and, where reflected light interactswith incident light, may affect incident light as well). It will beunderstood that an optical element comprising a diffractive element ordiffractive surface may be configured to diffract some, or substantiallyall, of the light impinging on, passing through, or reflected from thatoptical element from a light source, or a, or a lens, or a grating, orother source. It will be understood that a light source may beconfigured may direct some, or substantially all, of its emitted lightonto a sample, or onto a surface, or onto or through a lens, or agrating, or a slit, or a hole, or other object, optical element, orlocation.

In embodiments, the device may be an optical measurement device. Inembodiments, the device may be an optical imaging device. Inembodiments, the device may be configured to measure or detect opticalintensity. In embodiments, the device may be configured to measure ordetect absorbance of light. In embodiments, the device may be configuredto detect or measure spectral information from light passing through, orreflected from, or diffracted by, or emitted from, a sample or portionthereof. In embodiments, the device may be configured to detect ormeasure light scattering information from light passing through, orreflected from, or diffracted by, or emitted from, a sample or portionthereof. In embodiments, the device may be configured to detect ormeasure polarization information from light passing through, orreflected from, or diffracted by, or emitted from, a sample or portionthereof. In embodiments, the device may be configured to detect ormeasure other optical information from light passing through, orreflected from, or diffracted by, or emitted from, a sample or portionthereof.

In embodiments, a device configured for operation in may comprise alight source, and may include a light source lens (or lenses) configuredto direct light from said light source onto a first optical elementmounted on a rotatable mount. Light passing to and through a first lens(or first set of lenses) may be directed onto, and in embodiments may bedirected through, a sample (e.g., a sample held in or by a sampleholder). A mirror mounted on a rotatable mount may be used. Such lightmay be reflected to a reflective surface of a second optical element andthereby reflected and directed to a photodetector for observation,measurement, or analysis.

In embodiments, a light source of a unified detection device maycomprise a light source selected from an incandescent lamp, a flashlamp, a laser, a light-emitting diode, and an arc light. In embodiments,a unified detection device as disclosed herein may further comprise oneor more of a grating, an aperture, a filter, and a polarizer. Inembodiments, a photodetector of a unified detection device as disclosedherein may comprise an optical component selected from a photodiode, aphotomultiplier, a charge-coupled device (CCD), a spectrophotometer, acamera, and a microscope.

The devices, systems, and methods disclosed herein provide multipleoptical capabilities in a single device or system. Devices disclosedherein are capable of performing spectroscopic, fluorescence, andluminescence observations, measurements and analyses; systems includingthese devices are also capable of performing all such opticalobservations, measurements and analyses. Provision of such multiplecapabilities in a single device or in a single system may eliminate theneed to move or load a sample in multiple devices when subjecting asample to multiple analyses; thus, devices, systems and methodsdisclosed herein may provide greater accuracy, precision, and speed ofsample analysis. Eliminating the need to load a sample on multipledevices for multiple analyses may reduce degradation of a sample wherethe time to perform multiple analyses is reduced as compared to priordevices, systems, or methods requiring use of multiple devices orsystems. Provision of such multiple capabilities in a single device orin a single system may thus simplify and streamline the observation,measurement, and analysis of samples. Provision of such multiplecapabilities in a single device or in a single system may reduce thetime required, and may reduce the cost of, the observation, measurement,and analysis of samples. Providing such multiple capabilities in asingle device or in a single system may simplify the design andoperation of machines and systems for observing, measuring, andanalyzing samples. Thus, devices, systems and methods disclosed hereinprovide greater ease, accuracy, precision, and speed of sample analysiswhile reducing the complexity and cost of such analyses. Accordingly,the devices, systems, and methods disclosed herein provide advantagesover prior devices, systems, and methods.

In one non-limiting example, a sample verification device is providedfor use with a sample container containing a sample. The devicecomprises at least one image capture device; a sample container support;and at least one communication module, wherein said at least one imagecapture device is aligned to collect visual information about at leastone characteristic of the sample and at least one sample identifierassociated with the sample whereby at least a portion of the informationis transmitted by the communication module where said information isprocessed to alert a user if the sample fails to meet one or more samplecollection criteria.

It should be understood that one or more embodiments herein may bemodified to have one or more of the following features. For example, thesample verification device may include a multi-axis image capture systemcomprising the at least one image capture device along a first axis andat least another image capture device along a second axis. Optionally, amulti-axis information capture system is provided comprising the atleast one image capture device along a first axis and at least anotherdata reader along a second axis. Optionally, a multi-angle informationcapture system comprising using the at least one image capture deviceand optical element to simultaneously image more than surface of thesample container. Optionally, a light controlled housing for containingat least a portion of the sample and at least a portion of the at leastone image capture device. Optionally, the light controlled housingcomprises a portion movable from a closed position to an open positionto allow for loading of the sample container into the sampleverification device. Optionally, a region of interest of the at leastone image capture devices comprises visualizing portions of at least twosample vessels. Optionally, a region of interest of the at least oneimage capture devices simultaneous images a portion of the sample andthe visual identifier on the sample vessel. Optionally, a region ofinterest of the at least one image capture devices simultaneous images aportion of the sample and a visual identifier on the sample vessel.Optionally, other embodiments may use an information storage unit usinga different technology such as but not limited to RFID to provideidentifier information. Identification elements, devices, or systems foridentifying and tracking samples may include but are not limited to barcodes and bar code readers; quick response (QR) code elements andreaders; near field communication (NFC) elements and readers;radiofrequency identification (RFID) elements and readers; and othersuch identification elements and readers currently known or to bedeveloped in the future. In such embodiment(s), an appropriate detectoror detectors can be used for obtaining the desired information about thesample or sample vessel.

In another non-limiting example, a method of performing sampleverification is provided, the method comprising capturing informationabout at least one characteristic of the sample; capturing at least onesample identifier associated with the sample; keeping the subject at thesample collection facility until sample verification is completed; andcommunicating an alert to a user if the sample fails to meet at leastone sample collection criteria, whereby a remedial action is takenbefore the subject departs from the sample collection facility.

It should be understood that one or more embodiments herein may bemodified to have one or more of the following features. For example, themethod may further comprise placing the sample into a light-controlledimaging location. Optionally, the method of capturing comprisesmulti-axial imaging. Optionally, the method of comprises multi-angleimaging. Optionally, the method of capturing comprises multi-angleimaging using a single capture device. The single imager may use anoptical element such as a dichroic or mirror to obtain imagery of aportion of the sample not directly in the linear line of sight of theimage capture device. The method of data and sample capture may besimultaneous or from same collection event. Sample verification mayinvolve characterizing two or more characteristics of the sample andthis analysis may occur onboard the sample collection device or on adevice or processor external to the verification device. Optionally, asystem may be provided with a sample integrity data logger or otherlongitudinal tracking capability to establish a record of the samplesbeing collected based on a certain selection criteria such as but notlimited to the technician performing the collection, patientinformation, volume of sample being collected, time of day the sample isbeing collected, geography of the collection, or other external datathat may be relevant to analysis of the collection event. Optionally,sample integrity can be determined based on at least one pre-selectedset of sample characteristics. Some embodiments may also include atemperature sensor to determine by direct contact, by laser, or otherindirect method the current temperature of the sample vessel or thesample therein. Optionally, some embodiments may substitute one or moreof the image capture devices with a smart phone that has a cameramounted in a slot or adapter of the sample verification device.Optionally, this additional camera may be additive to the cameras in thesample verification device. In such an embodiment, the sampleverification device may be in wireless or wired communication with thesmart phone camera to provide coordination of the data capture. Thesmart phone camera may capture an image of a different angle of thesample. Optionally, the smart phone camera may be mounted in a slot thatprovides a different angled view. Optionally, the smart phone is mountedexternal to the sample verification device but is in opticalcommunication with an optical train that provides the smartphone camerawith a view at a desired region of interest. A flash or other lightsource from may also be used with the sample verification device.Optionally, some embodiments of the sample verification device do notprovide any data capture, machine reader, or other imaging sensor builtinto the device, but instead, functions more as a jig to position asmart phone or other mobile computing device with at least one camera tocapture information about the sample. Such an embodiment may function toconsistently position the sample and/or provide a controlled lightenvironment for image capture. Optionally, some embodiments may includeonly one data capture or non-image capturing data reader and relies onthe smart phone for other capture capabilities. Optionally, someembodiments may use optical elements such as mirrors, fiberoptics, lightguides, or the like to utilize both front and back facing cameras on asmart phone to provide multiple images of the sample vessel. In someembodiments, a barcode or other graphic data code is place only on aside of sample that will also be imaged for sample verification so thata single can do image capture and ID capture; the barcode or othergraphic data code can be in the region of interest for sampleverification or at a location away from the region of interest but stillcapturable in the field of view by a single camera so that the ID orother information for the sample can be recorded. Optionally, thecondition of the sample in the sample vessel can be ascertained withoutother further analysis of the sample. Optionally, the condition of thesample in the sample vessel can be ascertained without chemical analysisof the sample. Optionally, the condition of the sample in the samplevessel can be ascertained without analyte testing of the sample.Optionally, the condition of the sample in the sample vessel can beascertained without removal of the sample from the sample vessel.

In yet another embodiment described herein, a method is provided ofperforming two or more laboratory tests with a small volume bodily fluidsample from a single subject, the method comprising: obtaining at asample collection site at least a first vessel containing a firstportion of a sample and a second vessel containing a second portion ofthe sample, wherein the sample is a small volume bodily fluid samplecollected from a single subject, and wherein the total volume of thesample collected from the single subject is no greater than 400microliters; transporting the first vessel and the second vessel fromthe sample collection site to a sample receiving site; and performing atthe sample receiving site one or more steps of a first laboratory testwith at least a portion of the first portion of the sample and one ormore steps of a second laboratory test with at least a portion of thesecond portion of the sample. Optionally, a sample verification step mayoccur prior to the transporting step. Optionally, the first portion ofthe sample and the second portion of the sample each comprise ananticoagulant. Optionally, the anticoagulant in the first portion of thesample differs from the anticoagulant in the second portion of thesample. Optionally, the anticoagulant in the first portion of the sampleis EDTA and the anticoagulant in the second portion of the sample isheparin. Optionally, the sample collection site and sample receivingsite are separated by at least 1 kilometer. Optionally, the first vesseland second vessel arrive at the sample receiving site no more than 12hours after the bodily fluid sample was obtained from the subject.Optionally, the sample is obtained from the subject's digit, which hasbeen punctured to release the sample from the subject. Optionally, thefirst portion of the sample is maintained in liquid form during thetransporting of the first vessel from the sample collection site to thesample receiving site.

In yet another embodiment described herein, a method is provided forperforming two or more laboratory tests with a small volume bodily fluidsample from a single subject, the method comprising: obtaining at asample collection site at least a first vessel containing a firstportion of a sample and a second vessel containing a second portion ofthe sample, wherein the sample is a small volume bodily fluid samplecollected from a single subject, and wherein the total volume of thesample collected from the single subject is no greater than 400microliters; transporting the first vessel and the second vessel fromthe sample collection site to a sample receiving site; removing at thesample receiving site from the first vessel a first vessel originalsample, wherein the first vessel original sample is at least a portionof the first portion of the sample; generating a first vessel dilutionsample from the first vessel original sample, wherein the first vesseldilution sample: i) is diluted at least 3-fold as compared to the firstvessel original sample, and ii) has a total volume of no more than 1000microliters, and performing at the sample receiving site one or moresteps of a first laboratory test with at least a portion of the firstvessel dilution sample and one or more steps of a second laboratory testwith at least a portion of the second portion of the sample. Optionally,a sample verification step may occur prior to the transporting step.Optionally, the first portion of the sample and the second portion ofthe sample each comprise an anticoagulant. Optionally, the anticoagulantin the first portion of the sample differs from the anticoagulant in thesecond portion of the sample. Optionally, the anticoagulant in the firstportion of the sample is EDTA and the anticoagulant in the secondportion of the sample is heparin. Optionally, the sample collection siteand sample receiving site are separated by at least 1 kilometer.Optionally, the first vessel and second vessel arrive at the samplereceiving site no more than 12 hours after the bodily fluid sample wasobtained from the subject. Optionally, the sample is obtained from thesubject's digit, which has been punctured to release the sample from thesubject. Optionally, the first portion of the sample is maintained inliquid form during the transporting of the first vessel from the samplecollection site to the sample receiving site.

Optionally, a method is provided comprising at least one technicalfeature from any of the prior disclosed features. Optionally, a methodis provided comprising at least any two technical features from any ofthe prior disclosed features. Optionally, a device comprising at leastone technical feature from any of the prior disclosed features.Optionally, device comprising at least any two technical features fromany of the prior disclosed features. Optionally, a system comprising atleast one technical feature from any of the prior disclosed features.Optionally, a system comprising at least any two technical features fromany of the prior disclosed features.

This Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used to limit the scope of the claimed subject matter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates one embodiment of a system including one embodimentof a device as disclosed herein.

FIGS. 2 to 4 show various embodiments of a device as disclosed herein.

FIGS. 5 and 6 show top-down and bottom-up views of at least oneembodiment of the internal components of a device as disclosed herein.

FIGS. 7 and 8 show perspective views of at least one embodiment of theinternal components of a device as disclosed herein.

FIGS. 9 and 10 show side views of at least one embodiment of theinternal components of a device as disclosed herein.

FIG. 11 shows an exploded view of at least one embodiment of theinternal components of a device as disclosed herein.

FIGS. 12 to 13 show various views of at least one embodiment of theinternal components of a device as disclosed herein.

FIGS. 14 to 15 illustrate embodiments of methods including at least oneembodiment of a device as disclosed herein.

FIG. 16 shows a portion of an image of a sample according to at leastone embodiment as disclosed herein.

FIGS. 17 to 22 show other embodiments as described herein.

FIGS. 23A to 23D show various views of an adapter for a sample vessel(s)according to at least one embodiment as disclosed herein.

DETAILED DESCRIPTION

Description and disclosure which may aid in understanding the fullextent and advantages of the devices, systems, and methods disclosedherein may be found, for example, in PCT Application Ser. No.PCT/US13/58627, U.S. patent application Ser. No. 13/769,820 (filed Feb.18, 2013), Ser. No. 14/446,080 (filed Jul. 29, 2014), 62/210,968, and62/237,527, the disclosures of which are all hereby incorporated byreference in their entirety for all purposes. The publications discussedor cited herein are provided solely for their disclosure prior to thefiling date of the present application. Nothing herein is to beconstrued as an admission that the presently disclosed systems, devices,and methods are not entitled to antedate such publication by virtue ofprior invention.

This document contains material subject to copyright protection. Thecopyright owner (Applicant herein) has no objection to facsimilereproduction of the patent documents and disclosures, as they appear inthe US Patent and Trademark Office patent file or records, but otherwisereserves all copyright rights whatsoever. The following notice shallapply: Copyright 2014-2015 Thermos, Inc.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive, as claimed. It may be noted that, as used inthe specification and the appended claims, the singular forms “a”, “an”and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a material” may includemixtures of materials, reference to “a compound” may include multiplecompounds, and the like.

As used in the description herein and throughout the claims that follow,the meaning of “or” includes “and/or” (i.e., “or” includes both theconjunctive and disjunctive) unless explicitly stated otherwise, orunless the context expressly dictates otherwise.

As used in the description herein and throughout the claims that follow,the meaning of “in” includes “in” and “on” unless the context clearlydictates otherwise.

References cited herein are hereby incorporated by reference in theirentirety, except to the extent that they conflict with teachingsexplicitly set forth in this specification.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, if a device optionally contains a feature for a samplecollection unit, this means that the sample collection unit may or maynot be present, and, thus, the description includes both structureswherein a device possesses the sample collection unit and structureswherein sample collection unit is not present.

As used herein, the terms “substantial” means more than a minimal orinsignificant amount; and “substantially” means more than a minimally orinsignificantly. Thus, for example, the phrase “substantiallydifferent”, as used herein, denotes a sufficiently high degree ofdifference between two numeric values such that one of skill in the artwould consider the difference between the two values to be ofstatistical significance within the context of the characteristicmeasured by said values. Thus, the difference between two values thatare substantially different from each other is typically greater thanabout 10%, and may be greater than about 20%, preferably greater thanabout 30%, preferably greater than about 40%, preferably greater thanabout 50% as a function of the reference value or comparator value.

As used herein, a “sample” may be but is not limited to a blood sample,or a urine sample, a tissue sample (e.g., a biopsy sample or a tissueslice), or other biological sample, however obtained or prepared. Ablood sample may be, for example, obtained from a finger-stick, or fromvenipuncture, or an arterial blood sample, and may be whole blood,serum, plasma, or other blood sample. Further examples of samplesinclude, without limitation, a water sample, a soil sample, a foodsample, an air sample; or other sample (e.g., a stool sample, a throatswab, a nasal swab or nasopharyngeal wash, a sample of saliva, urine,tears, gastric fluid, spinal fluid, mucus, sweat, earwax, oil, glandularsecretion, cerebral spinal fluid, tissue, semen, cervical fluid, vaginalfluid, synovial fluid, breath, hair, finger nails, skin, biopsy,placental fluid, amniotic fluid, cord blood, lymphatic fluids, cavityfluids, sputum, mucus, pus, microbiota, meconium, breast milk or othersecretion or excretion).

Thus, as used herein, a “sample” includes a portion of a blood, urine,or other biological sample, may be of any suitable size or volume, andis preferably of small size or volume. In some embodiments of thesystems, assays and methods disclosed herein, measurements may be madeusing a small volume blood sample, or no more than a small volumeportion of a blood sample, where a small volume comprises no more thanabout 5 mL; or comprises no more than about 3 mL; or comprises no morethan about 2 mL; or comprises no more than about 1 mL; or comprises nomore than about 500 μL; or comprises no more than about 250 μL; orcomprises no more than about 100 μL; or comprises no more than about 75μL; or comprises no more than about 50 μL; or comprises no more thanabout 35 μL; or comprises no more than about 25 μL; or comprises no morethan about 20 μL; or comprises no more than about 15 μL; or comprises nomore than about 10 μL; or comprises no more than about 8 μL; orcomprises no more than about 6 μL; or comprises no more than about 5 μL;or comprises no more than about 4 μL; or comprises no more than about 3μL; or comprises no more than about 2 μL; or comprises no more thanabout 1 μL; or comprises no more than about 0.8 μL; or comprises no morethan about 0.5 μL; or comprises no more than about 0.3 μL; or comprisesno more than about 0.2 μL; or comprises no more than about 0.1 μL; orcomprises no more than about 0.05 μL; or comprises no more than about0.01 μL.

As used herein, an “optical detector” detects electromagnetic radiation(e.g., light). An optical detector may detect an image or be used withan image, or may detect light intensity irrespective of an image, orboth. An optical detector may detect, or measure, light intensity. Someoptical detectors may be sensitive to, or restricted to, detecting ormeasuring a particular wavelength or range of wavelengths. For example,optical detectors may include, for example, photodiodes (including,e.g., avalanche photodiodes), photomultipliers, charge-coupled devices(CCDs), spectrophotometers, cameras, microscopes, and other devices(e.g., phototransistors, phototubes, photoresistors, photovoltaics, andother light-sensitive components, elements, and devices, embodying anysuitable technology (including, e.g., complementary metal oxidesemiconductor (CMOS), N-type metal oxide semiconductor (NMOS), thin-filmtransistor (TFT), and other technologies)) which detect light or measurelight intensity (of a single wavelength, of multiple wavelengths, or ofa range, or ranges, of wavelengths of light), form an image, or both.

As used herein, the term “microscopy” refers to optical methods whichinvolve imaging a sample, and which typically involve magnification,enlargement, or other techniques in order to provide a magnified imageof a sample or portion of a sample. Microscopy may involve one or moreof fluorescence microscopy, dark field microscopy, bright fieldmicroscopy, interference contrast microscopy, phase contrast microscopy,and other microscopy methods to image, observe, or measure one or moreportions of a sample or attributes of a sample or portion thereof. Suchmethods may, e.g., provide morphometric information regarding cells,particles, or other portions or constituents of a sample. Suchinformation may be measured quantitatively. In some embodiments, forquantitative microscopy, a sample is analyzed by two or more ofquantitative fluorescence microscopy, quantitative dark fieldmicroscopy, quantitative bright field microscopy, and quantitative phasecontrast microscopy. Quantitative microscopy may include use of imageanalysis techniques and/or statistical learning and classificationmethods to process images obtained by microscopy.

A sample to be analyzed, e.g., by optical or imaging means, may be heldin a sample holder for analysis. For example, a cuvette may serve assuch a sample holder. Other sample holding devices may also be used inplace of or in combination with a cuvette. For example, a microscopeslide may serve as a sample holder; a tube may serve as a sample holder;a clamp may serve as a sample holder; a receptacle may serve as a sampleholder; a surface may serve as a sample holder; or other object,implement, or device may serve to hold a sample, or portion thereof, foroptical observation, measurement, or analysis.

Similarly, and without limitation, other elements may be mounted onrotatable or otherwise movable mounts, in order that, for example, alens, or filter, or prism, slit, pin-hole, or other optical element canbe moved in order to adjust the placement of that element in the lightpath, or to remove the element from the light path. For example, suchmovement may include rotation (e.g., around an axle or other mount),transverse motion (e.g., along a direction substantially perpendicularto a light path), longitudinal motion (e.g., along a directionsubstantially parallel to a light path), other lateral motion, or acombination thereof. Such movement may be useful to make minoradjustments or corrections in position or orientation of the opticalelement; may be useful to make substantial changes in the position ororientation of the optical element (e.g., movement of the opticalelement into, or out of, an optical path); or combinations thereof.

An optical detector such as but not limited to a photodiode, a CCD, orother optical detector may be configured for use in both a digital(e.g., counting) mode and an analog mode, and may be configured toswitch between these modes as needed for a particular application or aparticular observation, measurement, or analysis.

Further elements which may be included in devices and systems disclosedherein, or which may be used in conjunction with devices and systemsdisclosed herein, include, for example, a fluid handling device orsystem that is configured to transport a sample, a sample holder, orother object or container to the measuring area. Further elements whichmay be included in devices and systems disclosed herein, or which may beused in conjunction with devices and systems disclosed herein, include,for example, a pipette and gantry system that prepares the samples, ortransports them to the measuring area. Devices and systems disclosedherein may include, or may be used in conjunction with, identificationelements, devices, or systems for identifying and tracking samples(e.g., bar codes and bar code readers; quick response (QR) code elementsand readers; near field communication (NFC) elements and readers;radiofrequency identification (RFID) elements and readers; and othersuch identification elements and readers).

In embodiments, a mirror, lens, optical element, or other component of aunified detection device or system may be mounted so as to be rotatable(or otherwise adjustable). Such rotatable or otherwise adjustablemounting configurations may utilize a rotor; an axle; a pivot; a hinge;a bearing; a belt; a slide or way; a cam; or other movable (includingslidable) part. Such rotatable or otherwise adjustable mountingconfigurations may include a motor (including a stepping motor); a screwor other threaded component; a piston; a piezoelectric actuator orpositioner; a pneumatic or hydraulic positioner or drive; or othermotive element. Such rotatable or otherwise adjustable mountingconfigurations may include tubing, wiring, springs, tensioners, gaskets,attachment elements such as clamps, bolts, glue, fasteners, frictionplates, supports, and other mechanical and structural elements.

Referring now to FIG. 1, at least one embodiment of system 10 having asample verification device 12 will now be described. As seen in FIG. 1,a sample 14 is collected from the subject S by a medical staff person M.It should be understood that other techniques for sample acquisition arenot excluded. In this non-limiting example, the sample 14 can beinserted into or otherwise operably engaged with or positioned tooperate with the sample verification device 12. FIG. 1 shows that thesample verification can be coupled by a wired connection 16 or othercommunication channel with a computer 18. Optionally, wireless,bluetooth, RF, NFC, 3G, 4G, 4GLTE, WiMax, other current or futurecommunication protocol, or other non-wired communication link can alsobe used. Although FIG. 1 shows the sample verification device 12 and thecomputer 18 as separate device, it should be understood some embodimentsmay combine both into one hardware unit, one functional unit, or thelike. Some embodiments may include at least one processor in the sampleverification device 12 to provide some capability to assess the sample,image of the sample, and/or data from the sample. Some embodiments mayinclude one or more data capture facilities in the computer to captureinformation about one or more characteristics of the sample(s).

In one non-limiting example, a system 10 may optionally include a remotecomputing resource 20, such as but not limited to a server or otherexternal computing device, which may be operably in communication withthe device 12 or computer 18 via communication channels 22 or 24respectively, effective that information obtained by the imager pursuantto its observation, measurement or analysis of samples may becommunicated to a user, an external device, a database, a network, orother device or system. A user, external device, network, or otherdevice or system may monitor, or may provide oversight of, theverification device 12 or its operation via a communication device inthe device or through the computer 18, via communication channels 22 or24 respectively. In one non-limiting example, a communication device anda communication channel may be effective to provide instructions to, orto otherwise control the operation of the verification device 12. Acommunication device or a communication channel may be present, and maybe used, in addition to, or in place of, a communication component or acommunication channel which may be included in a sample verificationdevice 12 as disclosed herein. In one non-limiting example, theverification device 12 can be viewed as a data capture device and theanalysis of the data occurs off-board of the device 12, such as but notlimited to being performed on an associated computer 18 or on a remotecomputing resource 20. In one non-limiting example, analysis of one ormore characteristics of the sample or samples occurs on-board theverification device 12. Optionally, some embodiments may be acombination of the foregoing wherein a portion of the analysis occurs onthe device 12 and a portion occurs off-board in an external device.Optionally, some embodiments may do substantially similar verificationof the sample at verification device 12 and at an offsite computingdevice to reduce the risk that one of the devices is not performing asdesired. In one non-limiting example, at least one portion of theverification occurs in a first time period and then a secondverification occurs in at least a second time period. In onenon-limiting example, the same verification is performed in at least thefirst and second time periods. Optionally, verification is differentbetween at least two of the time periods. Some embodiments may performsame or different verification over three or more time periods.

If an anomaly is detected, information about this anomaly can becommunicated to a user, medical professional, an external device, adatabase, a network, or other device, system, or personnel. In onenon-limiting example shown in FIG. 1, an alert, information about theanomaly, or an indicator can be sent to a display on computer 18, on thedevice 12, or to peripheral devices such a mobile computer, tabletcomputer 30, or smart phone 32. It should be understood that theinformation may be conveyed in a visual, audio, tactile, touch,vibration, other sensory manner to a recipient, or single or multiplecombinations of the foregoing. By way of non-limiting example,information being conveyed may be simple or basic, such as but notlimited to indicating an issue with the sample without being specific asto the issue. Optionally, some may be qualitative instead ofquantitative in the reporting. Optionally, some embodiments can beconfigured to provide at least some information about whatcharacteristic of the sample triggered the alert. By way of non-limitingexample, the alert may be sent by short message service (SMS), textmessage, email, voicemail, video call, or other message sendingprotocol, including those that may be developed in the future.Optionally, some embodiments can be configured to provide at least someinformation about what action to take next, be it corrective action orfollow-up action to verify the fault triggering condition. Optionally,some embodiments may be operated in a manual review mode where eachsample image is

Based on the sample characteristic(s) captured by the sampleverification device 12, the medical professional M or other personnelcan take action to rectify the issue. In one non-limiting example, thisinvolve collecting more sample from the subject S before the subject Sleaves the sample collection facility. This may involve repeating thecollection process, collecting only an additional portion desired toaddress any deficiency from the previous collection. Optionally, otherembodiments may have still further options related addressing sampleverification, such as but not limited user verification of the faultcondition or further processing of the sample so that it can be deemedacceptable without having to obtain further sample. Although many of theexamples herein describe the sample as a blood sample, it shouldunderstood that the sample from the subject is not limited to such bloodsamples and in some implementations, may be urine or other types ofsamples. In one non-limiting example, the sample verification device 12can be used to determine sample volumes and other basic informationabout the sample before the sample is further processed.

Referring now to FIGS. 2 to 4, one embodiment of a sample verificationdevice 12 will be described. FIG. 2 shows an embodiment of the sampleverification device 12 wherein the lid 50 is in a closed position. Insome embodiments, blocking ambient light can be useful to reducevariance in images or other data being collected about the sample. Inthis manner, the conditions of the imaging or other data collection canbe more consistent from sample to sample. Although the lid 50 in theclose position minimizes the amount of ambient light entering the device12, it should be understood that some alternative embodiments may nothave a lid that moves to fully close the interior of the device 12 fromexterior light and such embodiments are not excluded. Optionally, insuch embodiments, correction by way of software or other techniques maybe used to reduce variability between images.

FIG. 3 shows another view of one embodiment of a sample verificationdevice 12. In FIG. 3, the lid 50 is in an open position which allows forat least some internal components to be visualized in FIG. 3. In thisnon-limiting example, the lid 50 is movable in a slidable manner along arail 54. Some embodiments may include a sensor to detect if the lid 50is in the open or closed position. Optionally, some embodiments mayplace the sample container directly into an open slot a sampleverification device that does not have a lid. FIG. 3 also shows that inthe present embodiment, there is at least one imaging device 60 in thesample verification device 12 for characterizing one or more samplesthat may be in the device 12. Although FIG. 3 shows that the lid 50 issized to be essentially an entire side of the sample verificationdevice, some embodiments may use a smaller opening or cover that revealsonly a certain area sized to allow for insertion and removal of a sampleto be verified.

FIG. 4 shows a top-down view of one embodiment of the sampleverification device 12 with the lid 50 in the open position. FIG. 4shows a receiving location 70 in the sample verification device 12 wherethe sample(s) to be imaged may be placed. Although this embodiment showsthe location 70 as having a specific shape conforming to the outline ofthe sample vessel, it should be understood that other embodiments mayconfigure the receiving location 70 without having surfaces at thelocation 70 that conform to the shape of the sample vessel. Someembodiments may have a location 70 which a top-down shape such as butnot limited to square, rectangular, circular, oval, or the like. Someembodiments may have an adapter with an outer perimeter shape thatconfirms to the shape presented at location 70, but have an innerperimeter shape that is shaped to conform to that of the samplevessel(s). It should also be understood that some embodiments mayprovide a light source, light conduit, or other illumination source orguide 80 that can be positioned to light the sample placed at location70. An optical configuration in which the light source and the lightdetector are on opposite sides of an illuminated sample is termed a“backlit” configuration, in which the light source is configured tobacklight the sample. An optical configuration in which the light sourceand the light detector are on the same side of an illuminated sample istermed a “frontlit” configuration, in which the light source isconfigured to frontlight the sample. Although in this non-limitingexample the illumination source or light guide 80 is positioned tobacklight the sample, it should be understood that other embodiment mayuse both backlighting and frontlighting. Optionally, some embodimentsmay only use frontlighting. Others may use one or more lightingsource(s) at one or more off-angle positions, along with or in place ofany backlight or frontlight. It should also be understood that the typeof light used for illumination may also be pre-selected to have certainwavelength ranges and/or color temperature (as measured in Kelvin orother rating). Some embodiments may use fiberoptics or other opticalelements to guide light to the desired location. Some embodiments mayuse edge lighting techniques to illuminate the desire area(s).Optionally, others may place the light source directly at or adjacentthe desired location. Optionally, some embodiments may use one or morelight sources with a color rendition index rate of at least 90.Optionally, some embodiments may use one or more light sources with acolor rendition index rate of at least 92. Optionally, some embodimentsmay use one or more light sources with a color rendition index rate ofat least 95.

FIGS. 5 and 6 show top-down views of internal components of oneembodiment of the sample verification device 12. FIG. 6 shows acontainer 100 having one or more sample vessels therein positioned atlocation 70 for sample verification. The verification may be by way ofimaging through use of at least one imaging device 60. Although a cameramay be used as the imaging device 60, it should be understood that otherimage capture, image data, or data acquisition device that may bedeveloped in the future may be used or adapted for use as the imagingdevice 60.

Referring now to FIGS. 7 and 8, various perspective views of internalcomponents of the sample verification device 12. FIG. 7 shows a support110 such as but not limited to internal frame on which at least some ofthe internal components are mounted. In at least one non-limitingexample, there may be a platform portion 120 on which at least oneimaging device 60 can be mounted in alignment with location 70 tofacilitate sample verification. FIGS. 7 and 8 also show that a supportstructure such as but not limited to platform 120 can position thesample container 100 at a location so that a different portion of thesample container 100 can be imaged.

In one non-limiting example as seen in FIG. 9, at least another imagingdevice 130 can be positioned to view an underside surface of the samplecontainer 100 as indicated by arrow 132. In this non-limiting example,the sample verification device 12 uses a multi-axis imaging system tocapture image(s) along a first axis indicated by arrow 62 and alsocapture image(s) along a second axis indicated by arrow 132,simultaneously or sequentially. The non-limiting example of FIG. 9 usestwo cameras for imaging devices 60 and 130. It should be understood thatother embodiments may use a camera for one of the imaging devices and anon-imaging scanner such as but not limited barcode scanner for anotherof the data capture devices. Optionally, some embodiments may place theat least another imaging device 130 at another orientation in additionto or in place of the one shown to image a side surface, a top surface,a rear surface, or other surface of the sample vessel that may have avisual identifier. Optionally, an appropriately sized cut-out may beincluded in the platform 120 to allow for visualization of the targetsurface(s) which may have the detectable information. Optionally, otherembodiments may use other data communication techniques such as RFID orother techniques as described elsewhere herein in addition to or inplace of any visual identifying technique(s) used for the samplevessel(s). Information about the sample and/or sample vessel may beuploaded to a laboratory information system (LIS) or electronic medicalrecords (EMR) system to record if there are any issues to correct forregarding the sample or if the results (should the sample be processed)be discarded if sample quality or other issued is noted as being below athreshold for reliable accurate results. By way of non-limiting example,one LIS system that may be used with the sample integrity informationherein is described in U.S. application Ser. No. 14/341,745 filed Jul.25, 2014 and fully incorporated herein by reference. Optionally, thedevice herein with the imaging device 60 may be coupled to or integratedwith a sample processing device described in U.S. application Ser. No.13/769,820 filed Feb. 18, 2013 and fully incorporated herein byreference. Optionally, the device herein with the imaging device 60 maybe a stand-alone device for inspecting and/or performing formedcomponent separation that has communication capability, such as but notlimited to having hardware that allows the device to be internet-enabledthrough wired or wireless technology currently known or may be developedin the future.

Referring still to FIG. 9, it should be understood that in someembodiments, other cameras, optical sensors, and/or other detectors maybe used in addition to imaging device 60 to identify qualities about thesample. Some may use other detector technologies (not merely optical) tointerrogate the quality or integrity of the sample or the sample vessel.By way of non-limiting example, some embodiments may use at least one ofa spectrophotometer, an absorbance detector, a turbidimeter, a colorcamera, an infrared detector, a non-visual wavelength detector, or otherdetector technology currently known or may be developed in the future.In embodiments, these other detectors may be stacked above, adjacent, orotherwise positioned to allow for an alignment that allows forinterrogation of the sample or sample vessel. Some may opt for at leastone servo, a motor, or actuator to cause relative motion of the samplevessel and the at least one detector(s). Although other techniques arenot excluded, one embodiment may have an actuator rotate the samplevessel about an axis so that the detector may interrogate the samplewithout moving the detector. By way of non-limiting example, this may beachieved by a rotatable mount coupled to the platform, wherein abearing, bushing, or other interface allows for the mount to rotate. Therotatable mount may include a cutout, wire framing, or other design toallow for visualization of the sample. Optionally, some embodiments mayuse transparent or other material for the sample vessel mount thatallows for interrogation of the sample through the material. Optionally,another embodiment may have the detector mounted on a gantry and movethe detector relative to a stationary sample vessel.

Optionally as seen in FIG. 10, some embodiments may have an opticalelement 140 such as but not limited to a mirror, dichroic, prism, orother optical element(s) positioned to allow at least a single camera tocapture data from multiple surfaces of the target sample. By way ofnon-limiting example, one embodiment may have a mirror positioned belowthe location 70 but angled to allow the imaging device 60 tosimultaneous view more than one surface of the sample container 100.Optionally, some embodiments may have a movable optical element thatallows for control of when the other surface of the sample container 100is visible to the image capture device.

Referring now to FIG. 11, an exploded perspective view is shown ofvarious internal components of one embodiment of a sample verificationdevice 12. As seen in FIG. 11, most of the components are mounted to thesupport 110. Some embodiments may include additional support elementssuch as compressible, semi-compressible, or solid spacers 170 to mountselect components to the support 110.

FIGS. 12 and 13 show additional views of various internal components ofone embodiment of a sample verification device 12. Although mostembodiments shown herein such as that of FIG. 12 may have two cameras asthe imaging devices 60 and 130, it should understood that someembodiments may have only a single camera. Optionally, some embodimentsmay have an imaging device such as a camera at one angle and a machinecode reader or similar non-photo-based data capture device at anotherangle. Although embodiments herein show that the image capture or datacapture are aligned at orthogonally, it should be understood thatalignment along other angles are also workable. Optionally, FIG. 12 alsoshow that there may be one or more additional processor(s) on one ormore assembly(s) 180 that may provide for on-board analyticalcapabilities to analyze the captured data and/or contain wired,wireless, or both types of communication hardware to transmit the dataor an alert.

Sample Processing

Referring now to FIG. 14, one embodiment of bodily fluid samplecollection and transport system will now be described. FIG. 14 shows abodily fluid sample B on a skin surface S of the subject. In thenon-limiting example of FIG. 14, the bodily fluid sample B can becollected by one of a variety of devices. By way of non-limitingexample, collection device 1530 may be but is not limited to thosedescribed in U.S. Patent Application Ser. No. 61/697,797 filed Sep. 6,2012, which is fully incorporated herein by reference for all purposes.In the present embodiment, the bodily fluid sample B is collected by oneor more capillary channels and then directed into sample vessels 1540.The sample B forms through a wound that may be formed on the subject.This may be by way of fingerstick or wound created at other alternatesites on the body. A lancet, a needle, other penetrating device, orother technique may be used to release the bodily fluid sample from thesubject. By way of non-limiting example, at least one of the samplevessels 1540 may have an interior that is initially under a partialvacuum that is used to draw bodily fluid sample into the sample vessel1540. Some embodiments may simultaneously draw sample from the samplecollection device into the sample vessels 1540 from the same ordifferent collection channels in the sample collection device.Optionally, some embodiments may simultaneous draw sample into thesample vessels.

In the present embodiment after the bodily fluid sample is inside thesample vessels 1540, the sample vessels 1540 in their holder 1542 (oroptionally, removed from their holder 1542) are placed in the sampleverification device 12 as indicated by arrow 1543. Optionally, in someembodiments, the sample is centrifuged before or during image capture.Optionally, some other embodiments may use other formed componentseparation technique(s) currently known or developed in the future. Theformed component separation technique may optionally be used before orduring sample image capture. In this embodiment, the sample verificationdevice may have a lid the closes over the sample vessels 1540 while theyare processed. Optionally, some embodiment may not include a lid.

In the present embodiment after the sample verification is completed,the sample vessels 1540 in their holder 1542 (or optionally, removedfrom their holder 1542) are loaded into the transport container 1500. Inthis embodiment, there may be one or more slots sized for the samplevessel holder 1542 or slots for the sample vessels in the transportcontainer 1500. By way of non-limiting example, they may hold the samplevessels in an arrayed configuration and oriented to be vertical or someother pre-determined orientation. It should be understood that someembodiments of the sample vessels 1540 are configured so that they holddifferent amount of sample in each of the vessels. By way ofnon-limiting example, this can be controlled based on the amount ofvacuum force in each of the sample vessels, the amount of samplecollected in the sample collection channel(s) of the collection device,and/or other factors. Optionally, different pre-treatments such as butnot limited to different anti-coagulants or the like can also be presentin the sample vessels.

As seen in FIG. 14, the sample vessels 1540 are collecting sample at afirst location such as but not limited to a sample collection site. Byway of non-limiting example, the bodily fluid samples are thentransported in the transport container 1500 to a second location such asbut not limited to an analysis site. The method of transport may be bycourier, postal delivery, or other shipping technique. In manyembodiments, the transport may be implemented by having a yet anothercontainer that holds the transport container therein. In one embodiment,the sample collection site may be a point-of-care. Optionally, thesample collection site is a point-of-service. Optionally, the samplecollection site is remote from the sample analysis site.

Although the present embodiment of FIG. 14 shows the collection ofbodily fluid sample from a surface of the subject, other alternativeembodiments may use collection techniques for collecting sample fromother areas of the subject, such as by venipuncture, to fill the samplevessel(s) 1540. Such other collection techniques are not excluded foruse as alternative to or in conjunction with surface collection. Surfacecollection may be on exterior surfaces of the subject. Optionally, someembodiments may collect from accessible surfaces on the interior of thesubject. Presence of bodily fluid sample B on these surfaces may benaturally occurring or may occur through wound creation or othertechniques to make the bodily fluid surface accessible.

Referring now to FIG. 15, yet another embodiment is described hereinwherein bodily fluid sample can be collected from an interior of thesubject versus collecting sample that is pooled on a surface of thesubject. This embodiment of FIG. 15 shows a collection device 1550 witha hypodermic needle 1552 that is configured to collect bodily fluidsample such as but not limited to venous blood. In one embodiment, thebodily fluid sample may fill a chamber 1554 in the device 1550 at whichtime sample vessel(s) 1540 may be engaged to draw the sample into therespective vessel(s). Optionally, some embodiments may not have achamber 1554 but instead have very little void space other thanchannel(s), pathway(s), or tube(s) used to direct sample from the needle1552 to the sample vessel(s) 1540. For bodily fluid samples such asblood, the pressure from within the blood vessel is such that the bloodsample can fill the chamber 1554 without much if any assistance from thecollection device. Such embodiments may optionally include one or morevents, such as but not limited to a port, to allow air escape as thechannels in the collection device are filled with sample.

In the present embodiment after the bodily fluid sample is inside thesample vessels 1540, the sample vessels 1540 in their holder 1542 (oroptionally, removed from their holder 1542) are placed in the sampleverification device 12 as indicated by arrow 1543. In this embodiment,the sample verification device may have a lid the closes over the samplevessels 1540 while they are processed. Optionally, some embodiment maynot include a lid.

In the present embodiment after the sample verification is completed,the sample vessels 1540 in their holder 1542 (or optionally, removedfrom their holder 1542) are loaded into the transport container 1500.

At least some or all of the embodiments can have a fill indicator suchas but not limited to a view window or opening that shows when sample ispresent inside the collection device and thus indicate that it isacceptable to engage the sample vessel(s) 1540. Optionally, embodimentsthat do not have a fill indicator are not excluded. The filled samplevessel(s) 1540 may be disconnected from the sample collection deviceafter a desired fill level is reached. Optionally, additional samplevessel(s) 1540 can be engaged to the sample collection device 1550 (or1530) to collect additional amounts of bodily fluid sample.

In some embodiments, one or more cameras may be placed in the centrifugerotor such that it can image the contents of the centrifuge vessel whilethe rotor is spinning. The camera images may be analyzed and/orcommunicated in real time, such as by using a wireless communicationmethod. This method may be used to track the rate of sedimentation/cellpacking, such as for the ESR (erythrocyte sedimentation rate) assay,where the speed of RBC (red blood cell) settling is measured. In someembodiments, one or more cameras may be positioned outside the rotorthat can image the contents of the centrifuge vessel while the rotor isspinning. This may be achieved by using a strobed light source that istimed with the camera and spinning rotor. Real-time imaging of thecontents of a centrifuge vessel while the rotor is spinning may allowone to stop spinning the rotor after the centrifugation process hascompleted, saving time and possibly preventing over-packing and/orover-separation of the contents.

Referring now to FIG. 17, one embodiment of a centrifuge with a sampleimaging system will now be described. FIG. 17 shows that, in someembodiments, the imaging device 750 such as but not limited to a camera,a CCD sensor, or the like may be used with a centrifuge rotor 800. Inthis example, the imaging device 750 is stationary while the centrifugerotor 3800 is spinning. Imaging may be achieved by using a strobed lightsource that is timed with the camera and spinning rotor. Optionally,high speed image capture can also be used to acquire images without theuse of a strobe.

FIG. 18 shows one embodiment of the imaging device 750 that can bemounted in a stationary position to view the centrifuge vessel while itis spinning in the centrifuge. FIG. 18 shows that in addition to theimaging device 750, illumination source(s) 752 and 754 may also be usedto assist in image capture. The mounting device 756 is configured toposition the imaging device 750 to have a field of view and focus thatenables a clear view of the centrifuge vessel and content therein. Inone embodiment, the device 750 may function either like imaging device60. Optionally, the device 750 may be used to function like detector 130to detect identifier information from the sample vessel. The device 750may be used to detect the identifier while the centrifuge is spinning.Optionally, the device 750 may be used in combination with thecentrifuge rotor with integrated camera 800 to have at least a twodetector system that can function similar to the multi-detector systemshown in FIG. 9. FIG. 18 can be used to combine the detectorcapabilities of a device such as that of FIG. 9 with a centrifuge.

Referring now to FIGS. 19 to 21, yet another embodiment of a centrifugewith a sample imaging system will now be described in an integrateddevice. By way of non-limiting example, FIG. 19 can be used to combinethe detector capabilities of a device such as that of FIG. 9 with acentrifuge. FIG. 19 shows that, in some embodiments, the imaging device770 such as but not limited to a camera, a CCD sensor, or the like maybe mounted inside or in the same rotation frame of reference as thecentrifuge rotor 800. FIG. 20 shows a cross-sectional view showing thatthe imaging device 770 is positioned to view into the sample in thecentrifuge vessel 772 through an opening 774 (shown in FIG. 21). Becausethe imaging system is in the centrifuge rotor 800, the imaging systemcan continuously image the centrifuge vessel 772 and the sample thereinwithout the use of a strobe illumination system. Optionally, thecentrifuge rotor 800 can be appropriately balanced to account for theadditional weight of the imaging device 770 in the rotor. Optionally,some embodiments may combine both the embodiments of FIG. 18 with one ofthe embodiments from FIGS. 19 to 21 to combine the detector capabilitiesof a device such as that of FIG. 9 with a centrifuge. Optionally, stillother detectors may be combined with a combined formed componentseparator and detector, such as but not limited one or more of aphotodiode, a photomultiplier, a charge-coupled device (CCD), aspectrophotometer, a camera, a microscope, an absorbance detector, aturbidimeter, a color camera, an infrared detector, a non-visualwavelength detector, or other detector technology currently known or maybe developed in the future.

Referring now to FIG. 22, it should be understood that in someembodiments a cartridge 9800 may have at least one observation port,opening, transparent area, or other area 9821 that allows forinterrogation of the sample vessel(s) that are held by cartridge 9800that has at least some of the reagents and/or consumables to be used inassay performance. FIG. 22 shows one embodiment of a cartridge 9820 thatis received into an assay station receiving location 9830 of the systemsuch as but not limited to a sample processing device as described inU.S. patent application Ser. No. 13/769,820 filed Feb. 18, 2013 andfully incorporated herein by reference for all purposes. In someembodiments, an assay station receiving location may be a tray. In thisnon-limiting example, the assay station receiving location 9830 hasslots 9832 that are shaped to receive rails 9834 on the cartridge 9820.The cartridge 9820 is inserted into the assay station receiving location9830 until the cartridge 9820 engages a stop 9836. It should beunderstood that the regions in FIG. 22 and optionally in othercartridges described herein, the region may contain a plurality ofwells, tips or the like such as shown in the cartridges of U.S. Pat. No.8,088,593 fully incorporated herein by reference for all purposes.

Referring now to FIGS. 23A to 23C, it should be understood that someembodiments herein may use an adapter 2000 to facilitate placement of asample container into a formed component separation device such as butnot limited to a centrifuge. Although this embodiment shows the adapter2000 has a cylindrical shape conforming to the outline of the centrifugevessel holder, it should be understood that other embodiments mayconfigure the receiving location centrifuge vessel holder to be ofdifferent shapes. Some embodiments may have a receiving location which atop-down shape such as but not limited to square, rectangular, circular,oval, or the like and the adapter 2000 can be shaped to conform to thatshape. Some embodiments may have an adapter with an outer perimetershape that confirms to the shape presented at a receiver such as acentrifuge holder, but have an inner perimeter shape that is shaped toconform to that of the sample vessel(s).

As seen in FIG. 23C, the central axis of the cutout 2010 can be at anangle relative to the central axis of the insert 2000. Optionally, someembodiments may align these two axis to be parallel. Having the angledconfiguration for cutout 2010 can be beneficial to create a morehorizontal orientation during centrifugation so that the meniscus of thepacked formed components can have a more horizontal configuration(instead of angled) when the container is removed from adapter 2000 andthe vessel is vertically oriented. In this manner, the meniscus will beperpendicular to a longitudinal axis of the vessel. This minimizes therisk of an inaccurate aspiration because of an angled meniscus causingan incomplete aspiration.

As seen in FIG. 23A, the cross-sectional shape of the cutout 2010 can beconfigured to match an outer perimeter shape of the sample vessel. Itshould be understood that in some embodiments, the material of adapter2000 is transparent. Optionally, the material is a translucent material.Optionally, the sample vessel is one configured to be the same samplevessel that is used in sample collection so that there is no sample losttransferring the sample from a collection vessel to the centrifugationvessel. Herein, the shape of the cutout 2010 is designed to receive thecollection vessel so that there is no loss simply to have the formedcomponents separated. Herein, the shape of the cutout 2010 is designedto receive the collection vessel so that there is no loss simply to havethe sample centrifuged. As seen in FIG. 23C, some embodiments may have afurther hollowed-out area 2030.

Referring now to FIG. 23D, a side cross-sectional view is shown of acentrifuge rotor 2050 having two adapters 2000 therein. In thisembodiment, the centrifuge rotor 2050 rotates around a center axis 2052.The adapters 2000 in this embodiment slide into existing “slots” in thecentrifuge rotor 2050 but will angle the vessels to be held in adapter2000 to a desired orientation. Having the angled configuration forcutout 2010 in adapter 2000 can be beneficial to create a morehorizontal orientation of vessel during centrifugation so that themeniscus of the liquid portion and the boundary of the formed componentswill both be perpendicular to a longitudinal axis of the vessel.

Use in the Field

In one non-limiting example, one or more purposes for the sampleverification device can be to insure sample integrity prior to shippingor to insure sufficient sample is obtained prior to letting subjectleave. For example, the sample verification can be helpful if an issuecan be easily corrected by collecting another sample from the subject orthrough some other processing of the sample prior to shipment.Optionally, some embodiments may also include sample verification at thedestination location of the sample.

In one non-limiting example, the sample verification device may be usedat point-of-service locations in the field such as but not limited toretail store locations, pharmacies, private medical offices, doctoroffices, end user homes, or other sites that may be remote from aclinical laboratory. Of course, some non-limiting examples may also usesuch sample verification devices at a clinical laboratory or acollection facility that is a part of a clinical laboratory and such useis not excluded. In one non-limiting example, the sample verificationdevice is used to take images of samples after collection to determinesample volumes and other basic information about the sample before thesample is processed by clinical laboratory analysis hardware. This canhelp eliminate laboratory test error that results at the point of samplecollection and unrelated to processing of the sample on the clinicallaboratory analysis hardware. Although the embodiments herein areconcerned primarily with human samples, it should be understood thatsample from animals, samples from non-humans, and even non-biologicalsamples can be used with one or more the sample verification devicesherein.

In one non-limiting example, the sample verification device is used totake a photograph or digital image of a patient's blood sample at fieldlocations. The sample verification device also reads one or moreidentifiers such as but not limited to a barcode, QR code, or othermachine-readable non-letter type code on the sample container in orderto identify the sample. In this non-limiting example, the image of thesample can be processed by a computer program to determine informationabout the sample including if enough volume of blood is present forsuccessful testing. In embodiments, for example, the volume of thesample may be determined by detection of the upper surface of the volumeof sample held in the container (e.g., by detection of light scatteredfrom such a surface, or by detection of light intensity of color passingthrough the sample). In embodiments, for example, the volume of thesample may be determined by detection of the lower point within thesample container in which no sample is present (e.g., by detection oflight intensity, or color, or light scattering, or other opticalindication of the absence or presence of sample). In embodiments, forexample, the volume of the sample may be determined by measurement ofthe volume of container in which sample is present, or in which sampleis absent, e.g., by means indicated above, by detection of light passingthrough multiple portions of the container, or through substantially allof the container. If the sample is too small, the software can alert thetechnician that more blood must be drawn before the patient leaves theservice center. The same image of the sample may also includeinformation about the identifier(s).

Referring now to FIG. 16, by way of non-limiting example, one method ofverifying the sample may be to inspect an image of the sample.Optionally, one method is to measure multiple wavelengths of lightthrough absorbance or scattering. Optionally, some embodiments may useimage analysis using pre-designated areas of interest 1600, 1602, 1604,or calculated areas of interest in the image of sample to detect anyanomalies. Optionally, some embodiments may centrifuge the sample firstand then during or afterwards, look for pellet and total volume.Optionally, after centrifuge or other formed component separationtechnique(s) currently known or may be developed in the future, theportion of the image to be verified is the liquid portion that is abovea separator gel and/or the pellet of formed components that are at abottom portion of the sample vessel in area of interest 1604. In onenon-limiting example, the verification device can check for cell lysisby verifying the color of the liquid portion of the sample, such as inarea of interest 1602. The color can be compared against calibratedcolors deemed acceptable for plasma or similar liquid portion of thesample. Optionally, other sample quality issues such as foam on top,bubbles within the sample, or a non-horizontal meniscus in area ofinterest 1600. It should be understood that these areas of interests1600, 1602, and 1604 are exemplary and non-limiting. Other embodimentsherein may select other areas of interest or change the dimensions ofthe area of interest (wider, narrower, etc. . . . ).

In one non-limiting example, basic functionality of the sampleverification device comprises two or more of the following: captureimage(s) of at least one side of the sample container (for analysis) andthe bottom of the sample container (for barcode identification)simultaneously and send the result to a separate computing device; havean average processing time of 30 seconds or less; provide backlightingof the sample container for a consistently well-lit image captureenvironment; block ambient light to reduce variance in images; sense ifthe lid is open or closed to reduce human error when using the device;use indicator lights to communicate the device's status to the user atall times; use data communication and/or power interface such as but notlimited to a single micro USB input for both power and communicationto/from the associated computer (it should be understood that futureinterfaces that satisfy the foregoing are not excluded); or have ananti-theft feature such as but no limited to a keyhole compatible with astandard Kensington laptop lock to prevent theft in the patient servicecenter. In one embodiment, the overall geometry of the sampleverification device may have at least two or more of the following:footprint no larger than about 6″×6″; height no taller than about 12″;weight no greater than about 5 kg. Internally, in one non-limitingexample, the sample verification device is configured to have at least0.5″ of clearance on either side of the sample container when the samplecontainer is inserted into the sample verification device.

In one non-limiting example, the camera used as the imaging device hasat least two or more of the following: a minimum resolution of 1024×768pixels; be powered and transmit data using at least USB 2.0 or higher;have the ability to take images within 2 seconds; or consume no morethan 200 mA maximum. Optionally, some embodiments may communicate by waywireless protocol such as but not limited to Bluetooth LE, Bluetooth,802.11 family of protocols, or other wireless data protocols. Someembodiments may also include cellular or other communications capabilitysuch as but not limited to 3G, 4G, 4GLTE, WiMax, or other current orfuture communication protocol. It should be understood that datatransmission techniques such as those developed in the future may beadapted for use with the sample verification device and are not excludedherein.

In one non-limiting example, a backlight for use as source 80 has atleast two or more of the following: an illuminated surface area of atleast 20 mm×20 mm; substantially uniform illumination across its entireworking surface area; consume no more than 100 mA maximum.

In one non-limiting example, the lid or other closeable portion of thesample verification device may have at least one lid position sensorhaving at least two or more of the following: detect when the lid isclosed within no more than 0.25″ of its fully closed position; relay thestatus of the door (open or closed) to a processor on the printedcircuit assembly (PCA); consume no more than 30 mA maximum.

In one non-limiting example, the sample verification device may have aPCA with two or more of the following: monitor the status of the lidposition sensor; have on/off control of the backlight; have control ofvisual displays such as but not limited to an LCD screen or visualindicators such as but not limited to RGB LED's to indicate devicestatus; work as a USB pass-through for the two cameras; use USB 2.0 orhigher USB protocol for both power and communication; allow for 24-hoursof continuous use in any state without overheating or malfunctioning.

In at least one non-limiting example, the sample verification device canhave at least two or more of the following: accommodate left and righthanded users (such as through a center positioning of the sample holdingarea that does not bias either type of user); allow for use whilewearing latex or other commonly used medical gloves wherein the use ofbuttons and other touch features on the device are not impaired by usersthat wear gloves; not damage the sample during use; allow for relativelyeasy cleaning of all potentially contaminated surfaces (e.g., byproviding smooth surfaces and avoiding grooves and edges which mayharbor contaminants); be composed of materials that are inert to thesample collection unit; be composed of materials that are easily cleanedin case of contamination from sample or user; be composed of materialsthat are durable; be absent of any sharp corners of edges that may existfrom machining or any other reason. Optionally, the sample verificationdevice may be configured to have a sample holder with recessed portions,fluid guides, overflow areas, or the like to move sample away from usercontact areas in case of sample spillage or other undesired release.

It should be understood that some embodiments may use the sampleverification device or portions of it as part of a system that mayinclude a sample handling device, which is operably connected to sampleverification device by a linkage effective that a sample (which may be asolid, fluid, gas, or other sample) is provided to the sampleverification device in a form and configuration suitable forobservation, measurement, or analysis by the sample verification device.

In embodiments, a sample handling device may include a linkage with thesample verification device, so that a separate linkage is not present,or is optional. A linkage of a sample handling device or a linkage maycomprise, for example, a loading port or guide which aids in properplacement of a sample (or sample holder in which a sample may beretained or enclosed); or may comprise, for example, a mechanical system(e.g., a sample handling device) configured to transport a sample orsample holder from a first location to a second location, where thesecond location is a location within the sample verification devicesuitable for observation, measurement, or analysis of the sample; or mayotherwise enable positioning of a sample or sample holder in a sampleverification device for observation, measurement, or analysis.

In embodiments, a sample handling device may include, or may be a partof, or may operate in conjunction with, a fluid handling device or afluid handling system. For example, a fluid handling device or systemmay be configured to transfer a sample, a sample holder, a reagentvessel, or other object or container to or within a sample verificationdevice. In embodiments, a fluid handling device or system may comprise apipette configured to uptake, dispense, or transfer a biological sample.A fluid handling device or system may include, or may be linked to,other components, devices, or systems. A fluid handling device or systemmay include a plurality of pipette heads (where an individual pipettehead includes a pipette nozzle configured to connect with a pipette tipthat is removable from the pipette nozzle); one or more plungers thatare individually movable, wherein at least one plunger is within apipette head and is movable within the pipette head; and a motorconfigured to effect independent movement of individual plungers of theplurality. In embodiments, a pipette nozzle may be configured to connectwith, or may include, an actuator configured to effect independentmovement of one or more individual plungers. In embodiments, a fluidhandling device or system may be configured to engage, or may include, asample holder; and at least one pipette head, wherein an individualpipette head comprises a pipette nozzle configured to connect with thesample holder that is removable from said pipette nozzle, wherein theapparatus is operably connected to an image capture device that isconfigured to capture an image within or through the sample holder. Inone non-limiting example, after sample verification is confirmed, thesample may be fluidically removed from the sample container by way of afluid handling device or a fluid handling system and transported onwardwithout the sample container to other location(s) for aliquoting,dilution, or other further processing.

While the systems, devices, and methods have been described andillustrated with reference to certain particular embodiments thereof,those skilled in the art will appreciate that various adaptations,changes, modifications, substitutions, deletions, or additions ofprocedures and protocols may be made without departing from the spiritand scope of the invention. By way of non-limiting example, although atleast some embodiments herein are shown as handling only a single samplecontainer at a time, it should be understood that other embodiments canbe configured to handle batches of sample containers simultaneously.Optionally, some embodiments may use a conveyor belt, a sequentialloading system, or other multi-vessel transport to send a plurality ofsamples simultaneously, a plurality of samples sequentially, or aplurality of single samples in a sequential manner into the sampleverification device.

Additionally, concentrations, amounts, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited.

While at least some embodiments systems, devices, and methods have beenshown and described herein, it will be obvious to those skilled in theart that such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. Any feature, whetherpreferred or not, may be combined with any other feature, whetherpreferred or not. The appended claims are not to be interpreted asincluding means-plus-function limitations, unless such a limitation isexplicitly recited in a given claim using the phrase “means for.”

1. A sample verification device for use with a sample containercontaining at least one sample, the device comprising: at least oneimage capture device; a sample container support; wherein said at leastone image capture device is aligned to collect visual information aboutat least one characteristic of the sample and using image processing todetect if the sample fails to meet one or more sample collectioncriteria.
 2. The sample verification of claim 1 further comprising amulti-axis image capture system comprising the at least one imagecapture device along a first axis and at least another image capturedevice along a second axis.
 3. The sample verification of claim 1further comprising a multi-axis information capture system comprisingthe at least one image capture device along a first axis and at leastanother data reader along a second axis.
 4. The sample verification ofclaim 1 further comprising a multi-angle information capture systemcomprising using the at least one image capture device and opticalelement to simultaneously image more than surface of the samplecontainer.
 5. The sample verification of claim 1 further comprising alight controlled housing for containing at least a portion of the sampleand at least a portion of the at least one image capture device.
 6. Thesample verification of claim 5 wherein the light controlled housingcomprises a portion movable from a closed position to an open positionto allow for loading of the sample container into the sampleverification device.
 7. The sample verification of claim 5 wherein aregion of interest of the at least one image capture devices comprisesportions of at least two sample containers.
 8. The sample verificationof claim 5 wherein a region of interest of the at least one imagecapture devices simultaneous images a portion of the sample and a visualidentifier on the sample container.
 9. The sample verification of claim5 wherein a region of interest of the at least one image capture devicessimultaneous images a portion of the sample and a visual identifier onthe sample container.
 10. A method of performing sample verificationcomprising: capturing information about at least one characteristic ofthe sample; capturing at least one sample identifier associated with thesample; keeping a subject at the sample collection facility until sampleverification is completed; communicating an alert to a user if thesample fails to meet at least one sample collection criteria, whereby aremedial action is taken before the subject departs from the samplecollection facility.
 11. The method of claim 10, comprising placing thesample into a light-controlled imaging location.
 12. The method of claim10 wherein capturing comprises multi-axial imaging.
 13. The method ofclaim 10 wherein capturing comprises multi-angle imaging.
 14. The methodof claim 10 wherein capturing comprises multi-angle imaging using asingle capture device.
 15. A method of sample verification comprisingusing an adapter to angle a sample vessel to a preferred orientationduring centrifugation; imaging the sample vessel after centrifugation.